Our long-range research goal is to define physiological regulation of gap junction (GJ)-mediated intercellular communication (GJIC) between pulmonary alveolar epithelial cells (AEC). GJs are paired heximeric assemblies (connexons) of integral membrane proteins (connexins; Cx) that couple cells via low resistance, gated axial pores. Our data show that AECs selectively regulate expression of Cx mRNAs and proteins, and that these assemble to form functional GJs and GJ plaques. Little is known, however, concerning distribution, regulation or functional significance of GJs in this essential lung cell population. The research objective is to investigate the role of extracellular matrix (ECM) in regulation of GJ expression and GJIC between adjacent AECs in primary culture. The central hypothesis is that GJIC is essential in both normal AECs and in lung injury. The approach involves two specific aims: I) to define the role of ECM fibronectin in regulation of connexin abundance in AECs in vitro and 2) to characterize the effects of ECM fibronectin on GJ plaque assembly and functional GJIC in AECs. Expertise in molecular and cell biology required to accomplish these goals is established in the laboratory and the applicant has begun to acquire these skills. Preliminary data and published observations demonstrate feasibility of the research, which will lead to more comprehensive understanding of ECM regulation of GJ expression, formation and function in AECs. These results will provide unique information essential to definition of mechanisms that underlie normal alveolar cell physiology, as well as the response of the lung to injury.